Carl June, via Getty

Carl June on CRISPR, CAR–T and how the Viet­nam War dropped him in­to med­i­cine

In Au­gust of 2011, Carl June and his team pub­lished a land­mark pa­per show­ing their CAR–T treat­ment had cleared a pa­tient of can­cer. A year-to-the-month lat­er, Jen­nifer Doud­na made an even big­ger splash when she pub­lished the first ma­jor CRISPR pa­per, set­ting off a decade of in­tense re­search and some­times even more in­tense pub­lic de­bate over the ethics of what the gene-edit­ing tool could do.

Last week, June, whose CAR–T work was even­tu­al­ly de­vel­oped by No­var­tis in­to Kym­ri­ah, pub­lished in Sci­ence the first US pa­per show­ing how the two could be brought to­geth­er. It was not on­ly one of the first time sci­en­tists have com­bined the ground­break­ing tools, but the first peer-re­viewed Amer­i­can pa­per show­ing how CRISPR could be used in pa­tients.

June used CRISPR to ed­it the cells of three pa­tients with ad­vanced blood can­cer, delet­ing the tra­di­tion­al T cell re­cep­tor and then eras­ing the PD–1 gene, a move de­signed to “un­leash” the im­mune cells. The ther­a­py didn’t cure the pa­tients, but the cells re­mained in the body for a me­di­an of 9 months, a ma­jor hur­dle for the ther­a­py.

End­points caught up with June about the long road both he and the field took to get here, if the treat­ment will ever scale up, and where CRISPR and oth­er ad­vance­ments can lead it.

The in­ter­view has been con­densed and edit­ed. 

You’ve spo­ken in the past about how you start­ed work­ing in this field in the mid-90s af­ter your wife passed away from can­cer. What were some of those ear­ly ef­forts? How did you start?

Well, I grad­u­at­ed from high school and had a low draft num­ber [for the Viet­nam War] and was go­ing to go to study en­gi­neer­ing at Stan­ford, but I was draft­ed and went in­to the Naval Acad­e­my in 1971, and I did that so I wouldn’t have to go to the rice fields.

The war end­ed in ’73, ’74, so when I grad­u­at­ed in 1975, I was al­lowed to go to med­ical school, and then I had a long term com­mit­ment to the Navy be­cause they paid for the Acadamy and Med­ical school. And I was in­ter­est­ed in re­search and at the time, what the Navy cared about was a small scale nu­clear dis­as­ter like in a sub­ma­rine, and like what hap­pened at Cher­nobyl and Fukushi­ma. So they sent me to the Fred  Hutchin­son Can­cer Cen­ter where I got trained in can­cer, as a med­ical on­col­o­gist. I was go­ing to open a bone mar­row trans­plant cen­ter in Bethes­da be­cause the Navy want­ed one in the event of a nu­clear cat­a­stro­phe.

And then in 1989, the Berlin Wall came down and there was no more Cold War. I had gone back to the Navy in ’86 for the trans­plant cen­ter, which nev­er hap­pened, so then I had to work in the lab full time. But in the Navy, all the re­search has to be about com­bat and ca­su­al­ty. They care about HIV, so my first pa­pers were on malar­ia and in­fec­tious dis­ease. And the first CAR-T tri­als were on HIV in the mid-90s.

David Porter

In ’96, my wife got di­ag­nosed with ovar­i­an can­cer and she was in re­mis­sion for 3-4 years. I moved to the Uni­ver­si­ty of Penn­syl­va­nia in 1999 and start­ed work­ing on can­cer be­cause I wasn’t al­lowed to do that with the Navy. My wife was ob­vi­ous­ly a lot of mo­ti­va­tion to do that. She passed away in 2001. Then I start­ed work­ing with David Porter on adop­tive trans­fer T cells.

I got my first grant to do CAR-T cells on HIV in 2004, and I learned a whole lot. I was lucky to have worked on HIV be­cause we did the first tri­als us­ing lentivirus­es, which is an en­gi­neered HIV virus.

I was trained in on­col­o­gy, and then be­cause of the Navy forced to work on HIV. It was ac­tu­al­ly a bless­ing in dis­guise.

So if you hadn’t been draft­ed, you would’ve be­come an en­gi­neer?

Yes. That’s what I was ful­ly in­tend­ing. My dad was a chem­i­cal en­gi­neer, my broth­er is an en­gi­neer. That’s what I thought I was go­ing to do. No one in my fam­i­ly was ever a physi­cian. It’s one of those many quirks of fate.

Back then, we didn’t have these ap­ti­tude tests. It was just hap­haz­ard. I ap­plied to three schools — Berke­ley, Stan­ford and Cal­tech — and I got in­to all three. It was just luck, fate.

And it turned out when I went to the Naval Acad­e­my, they had added a pre-med thing on­to the cur­ricu­lum the year be­fore, so that’s what I did when I start­ed, I did chem­istry.

I would’ve [oth­er­wise] been in nu­clear sub­marines. The most in­ter­est­ing thing in the Navy then was the nu­clear sub tech­nol­o­gy.

You talked about do­ing the first CAR-T tri­als on HIV pa­tients be­cause that’s where the fund­ing was. Was it al­ways in your head that this was even­tu­al­ly go­ing to be some­thing for can­cer?

So I got out of the Navy in ’99 and moved to Penn. I start­ed in ’98 work­ing on treat­ing leukemia, and then once I got to Penn, I con­tin­ued work­ing one day a week on HIV.

It’s kind of a Back-to-the-Fu­ture thing be­cause now can­cer has paved out a path to show that CAR–T cells can work and put down the man­u­fac­tur­ing and it’s go­ing to be a lot cheap­er mak­ing it for HIV. I still think that’s go­ing to hap­pen.

Jim Ri­ley, who used to be a post­doc in my lab, has some spec­tac­u­lar re­sults in mon­keys with HIV mod­els. They have a large NIH and NI­AID re­search pro­gram.

So we’re go­ing to see more and more of that. The CAR tech­nol­o­gy is go­ing to move out­side of can­cer, and in­to au­toim­mune and chron­ic in­fec­tions.

I want to jump over to cy­to­tox­ic re­lease syn­drome (CRS) be­cause a big part of the CRISPR study was that it didn’t pro­voke this po­ten­tial­ly dead­ly ad­verse ef­fect. When did you first be­come aware that CRS was go­ing to be a prob­lem?

I mean we saw it in the very first pa­tient we treat­ed but in all hon­esty, we missed it. I’m an MD, but I don’t see the pa­tient and David Porter took care of the first three pa­tients and our first pe­di­atric pa­tient, Emi­ly White­head.

In our first pa­tients, 2 out of 3, had com­plete re­mis­sion and there were fevers and it was CRS but we thought it was just an in­fec­tion, and we treat­ed with an­tibi­otics for 3 weeks and [even­tu­al­ly] it went away. And sort of mirac­u­lous­ly he was in re­mis­sion and is still in re­mis­sion, 9 years lat­er.

And then when we treat­ed Emi­ly. She was at a 106-de­gree fever over three days, and there was no in­fec­tion.

Tadamit­su Kishi­mo­to

I’ve told this sto­ry be­fore. My daugh­ter has rheuma­toid arthri­tis, and I had been pres­i­dent of the Clin­i­cal Im­mu­nol­o­gists So­ci­ety from 2009 to 2010, and the first good drug for ju­ve­nile rheuma­toid arthri­tis that came out. I was in­vit­ed to give the Japan­ese sci­en­tist Tadamit­su Kishi­mo­to the pres­i­den­tial award for in­vent­ing the drug.

Then in 2012, Emi­ly White­head was lit­er­al­ly dy­ing from CRS, she had mul­ti­ple or­gan fail­ures. And her labs came back and IL-6 lev­els were 1000x nor­mal. It turns out the drug I was look­ing at for my daugh­ter, it blocks IL-6 lev­els. I called the physi­cian and I said, ‘lis­ten there’s some­thing ac­tion­able here, since it’s in your for­mu­la­ry to give it to her off-la­bel.’

And she gave her the ap­pro­pri­ate dose for rheuma­toid arthri­tis. It was mirac­u­lous. She woke up very rapid­ly.

Now it’s co-la­beled. When the FDA ap­proved Kym­ri­ah, it was co-la­beled. It kind of saved the field.

How were you feel­ing dur­ing this time? Did you have any idea what was hap­pen­ing to her?

No, not un­til we got the cy­tokine lev­els, and then it was re­al­ly clear. The cy­tokine lev­els go up and it ex­act­ly co­in­cid­ed. Then we retroac­tive­ly checked out adults and they had ad­verse re­ac­tions and it easy to see. We hadn’t been on the look­out be­cause it wasn’t in our mouse mod­els.

And it ap­peared with those who got cured. It’s one of the first on-tar­get tox­i­c­i­ties seen in can­cer, a tox­i­c­i­ty that hap­pens when you get bet­ter. All the tox­i­c­i­ties from chemother­a­py are off-tar­get: like leukope­nia or hair loss.

I had a physi­cian who had a fever of 106,  I saw him on a fever when he was start­ing to get CRS. When the nurse came in and it said 106, they thought the ther­mome­ter must be bro­ken. On Mon­day, I saw him, and said “how are you feel­ing” and he said “fine.” And I looked at the ther­mome­ter and his tem­per­a­ture was still 102.

Peo­ple will will­ing­ly tol­er­ate on-tar­get tox­i­c­i­ty — that’s very dif­fer­ent from chemother­a­py — if they know it helps get them bet­ter. That’s a new prin­ci­ple in can­cer ther­a­py.

You had these ear­ly CAR–T re­sults al­most at the same time that Doud­na pub­lish­es the first CRISPR pa­pers, then still in bac­te­ria. When did you first start think­ing about com­bin­ing the two?

Yeah, it was pub­lished in Sci­ence in 2012 and that’s when Emi­ly White­head got treat­ed. It’s an amaz­ing thing.

That’s some­thing so or­thog­o­nal. You think ‘how in the heck can that ever ben­e­fit CAR–T cells?׳ but my lab had done the first edit­ed cells in pa­tients, pub­lished in 2012. And we used zinc-fin­gered nu­cle­as­es, which were the pre­de­ces­sors to CRISPR. It knocked out one gene at a time, but we showed it was safe.

I was al­ready in­to gene edit­ing be­cause it could make T cells re­sis­tant to HIV. So it was pret­ty ob­vi­ous that there were can­di­dates in T cells that you can knock out. And al­most every lab start­ed work­ing on some with CRISPR, cause it was much eas­i­er.

We were the first to get full ap­proval by the FDA, so we worked on it from 2012, had all the pre­clin­i­cal da­ta by 2016, and then it takes a while to de­vel­op a lot of new as­says for this as we were very cau­tious to op­ti­mize safe­ty and it took longer than we want­ed, but in the end, we learned a tremen­dous amount.

So what did we learn?

First of all our pa­tients had ad­vanced metasta­t­ic can­cer and had had a lot of chemother­a­py. The first pa­tient had had 3 bone mar­row trans­plants.

One thing is fea­si­bil­i­ty: could you re­al­ly do all the com­plex en­gi­neer­ing? So we found out we could. fea­si­bil­i­ty was passed.

An­oth­er was the fact that cas9 came out of bac­te­ria, forms of strep and staph. Every­one has pre-ex­ist­ing im­mu­ni­ty to Cas9 and we had ex­pe­ri­ence from the first tri­al with Sang­amo [with zinc-fin­ger nu­cle­as­es] where some pa­tients had a very high fever. In that case, we had used ade­n­ovirus­es, and it turned out our pa­tients had very high lev­els of base­line im­mune re­sponse to ade­n­ovirus­es, so we were wor­ried that would hap­pen with CRISPR, and it did not hap­pen.

It did not have any tox­i­c­i­ty. If it had, it would have re­al­ly set the field back. If there was an im­mune re­sponse to cas9 and CRISPR, there could’ve been a re­al bar­ri­er to the field.

And then, the cells sur­vived in the pa­tients. The fur­thest on, it was 9 months. The cells had a very high lev­el of sur­vival. In the pre­vi­ous tri­als, the cells sur­vived less than 7 days. In our case, the half-life was 85 days. We don’t know the mech­a­nism yet.

And we found very big pre­ci­sion in the mol­e­c­u­lar scis­sors, and that was a good thing for the field. You could cut 3 dif­fer­ent genes on 3 dif­fer­ent chro­mo­somes and have such high fi­deli­ty.

It [CRISPR] is liv­ing up to the hype. It’s go­ing to fix all these dis­eases.

What’s the po­ten­tial in CAR-T, specif­i­cal­ly?

Well there’s many many genes that you can add. There are many genes that knock­ing out will make the cells work bet­ter. We start­ed with the cell re­cep­tor. There are many, I think, aca­d­e­mics and biotechs do­ing this now and it should make the cells more po­tent and less tox­ic.

And more broad­ly, what else are you look­ing at for the fu­ture of CAR–T? The week be­fore your pa­per, there were the re­sults from MD An­der­son on nat­ur­al killer cells. 

Dif­fer­ent cell types, nat­ur­al killer cells, stem cells — putting CAR mol­e­cules in­to stem cells, macrophages. One of my grad­u­ate stu­dents start­ed a com­pa­ny to do CAR macrophages and macrophages ac­tu­al­ly eat tu­mor cells, as op­posed to T cells that punch holes in them.

There will be dif­fer­ent cell types and there will be many more ways to ed­it cells. The prime edit­ing and base edit­ing. All dif­fer­ent new vari­a­tions.

You’ve talked about how peo­ple used to think the im­muno-on­col­o­gy, if it ever worked, would nev­er­the­less be a bou­tique treat­ment. De­spite all the ad­vance­ments, No­var­tis and Gilead still have not met the sales they once hoped to grab from their CAR–T treat­ments. Are you con­fi­dent CAR–T will ever be wide­ly ac­ces­si­ble?

Oh yeah, No­var­tis’ sales are go­ing up. They had a hic­cup launch­ing.

Back in ’96 or ’97, when Genen­tech launched Her­ceptin, their com­mer­cial an­ti­body, they couldn’t meet the de­mand ei­ther and then they scaled up and learned how to do bet­ter cul­tures. So right now No­var­tis is us­ing tech in­vent­ed in my lab in the 1990s cul­ture tech that’s com­plex and re­quires a lot of la­bor, so the most ex­pen­sive part is hu­man la­bor. A lot can be made ro­bot­ic. The scale prob­lem will be much eas­i­er.

That’s an en­gi­neer­ing prob­lem that will be­come a thing of the past. The man­u­fac­tur­ing prob­lem will get a lot cheap­er. Here in the US, we have a huge prob­lem with how drugs are priced. We have a prob­lem with pric­ing. That’s a po­lit­i­cal is­sue.

But in cell ther­a­py, it’s just kind of the growth things you see in a new in­dus­try. It’ll get worked out.

This ar­ti­cle has been up­dat­ed to re­flect that Jim Ri­ley con­duct­ed work on CAR in HIV.  

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Kenneth Galbraith, incoming Zymeworks CEO

Zymeworks re­places half its C-suite, aims to lay off 25% of to­tal work­force as new CEO takes over

New Zymeworks CEO Kenneth Galbraith is aiming to hit the ground running when his tenure officially begins next month, but he’ll be doing so with a much different looking team.

In a lengthy press release outlining the biotech’s 2022 goals, Galbraith said Zymeworks will be laying off at least 25% of its staff over the course of the year. Half of its C-suite will also be replaced immediately as Galbraith looks to remake the company in his image after Ali Tehrani, Zymeworks’ founder and CEO since 2003, stepped down two weeks ago.

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.